̽��ֱ�� of Cambridge - biochemistry

Unexpected experiences: Katy Pitts describes preparing the department for her colleagues to return to the workplace

zs332 — Fri, 07 Aug 2020 08:00:00 +0000

Katy Pitts, Principal Assistant and Safety Officer at the Department of Biochemistry, could probably now write the How-To manual on re-opening a biochemistry department in a global pandemic. She tells us of the highs and lows of recent months – and how an encounter with ‘ ̽��ֱ��Distancer’ has (literally) opened doors for all.

Cambridge spin-out company wins £18m to fight Alzheimer's

plc32 — Thu, 24 Jan 2019 10:27:38 +0000

A biopharmaceutical company set-up by Cambridge academics from St John's College to develop drugs to treat illnesses such as Alzheimer's, Parkinson’s and more than 50 other related diseases has won £18 million in a Series A financing round.

Wren Therapeutics raised the funding from an international syndicate led by ̽��ֱ��Baupost Group with participation from LifeForce Capital and a number of high net worth individual investors.

Several of the company’s scientific founders are members of St John’s, including Professor Sir Christopher Dobson, Master of St John's, Professor Tuomas Knowles, a St John's Fellow, and Dr Samuel Cohen, the St John’s Entrepreneur in Residence.

Wren Therapeutics focuses on drug discovery and development for protein misfolding diseases such as Alzheimer’s and Parkinson’s and was founded in 2016.

Protein molecules form the machinery which carry out all of the executive functions in living systems. However, proteins sometimes malfunction and become misfolded, leading to a complex chain of molecular events that can cause long-lasting damage to the health of people affected and may ultimately lead to death.

This group of medical disorders are known as protein misfolding diseases. Alzheimer’s and Parkinson’s are widely recognised protein misfolding diseases, but others include type-2 diabetes, motor neurone disease and more than 50 other related illnesses.

Dr. Cohen explained: “Protein misfolding diseases are one of the most critical global healthcare challenges of the 21st century but are highly complex and challenging to address. Current strategies - in particular those driven by traditional drug discovery and biological approaches - have proven, at least to date, to be ineffective.

“Wren’s new and unique approach is instead built on concepts from the physical sciences and focuses on the chemical kinetics of the protein misfolding process, creating a predictive and quantitatively driven platform that has the potential to radically advance drug discovery in this class of diseases.”

Wren Therapeutics is a spin-off company from the ̽��ֱ�� of Cambridge and Lund ̽��ֱ�� in Sweden. ̽��ֱ��company is based at the ̽��ֱ�� of Cambridge, in the recently opened Chemistry of Health Centre, and plans on opening a satellite office in Boston, Massachusetts.

Professor Sir Christopher Dobson said: "Wren is built on many years of highly collaborative, uniquely integrated, interdisciplinary research that has uncovered the key molecular mechanisms associated with protein misfolding diseases.

"I am hugely enthusiastic about our ability to make tangible progress against these diseases and change the course of life for millions of people around the world suffering from these debilitating and increasingly common medical disorders.”

̽��ֱ��company will announce its board of directors shortly.

Wren Therapeutics secures £18 million in funding to tackle protein misfolding diseases.

"I am hugely enthusiastic about our ability to make tangible progress against these diseases"

Professor Sir Christopher Dobson

Dr Samuel Cohen, Entrepreneur in Residence at St John's and CEO of Wren Therapeutics

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Caterpillar found to eat shopping bags, suggesting biodegradable solution to plastic pollution

fpjl2 — Mon, 24 Apr 2017 15:52:27 +0000

Scientists have found that a caterpillar commercially bred for fishing bait has the ability to biodegrade polyethylene: one of the toughest and most used plastics, frequently found clogging up landfill sites in the form of plastic shopping bags.

̽��ֱ��wax worm, the larvae of the common insect Galleria mellonella, or greater wax moth, is a scourge of beehives across Europe. In the wild, the worms live as parasites in bee colonies. Wax moths lay their eggs inside hives where the worms hatch and grow on beeswax – hence the name.

A chance discovery occurred when one of the scientific team, Federica Bertocchini, an amateur beekeeper, was removing the parasitic pests from the honeycombs in her hives. ̽��ֱ��worms were temporarily kept in a typical plastic shopping bag that became riddled with holes.

Bertocchini, from the Spanish National Research Council (CSIC), collaborated with colleagues Paolo Bombelli and Christopher Howe at the ̽��ֱ�� of Cambridge’s Department of Biochemistry to conduct a timed experiment.

Around a hundred wax worms were exposed to a plastic bag from a UK supermarket. Holes started to appear after just 40 minutes, and after 12 hours there was a reduction in plastic mass of 92mg from the bag.

Scientists say that the degradation rate is extremely fast compared to other recent discoveries, such as bacteria reported last year to biodegrade some plastics at a rate of just 0.13mg a day. Polyethylene takes between 100 and 400 years to degrade in landfill sites.

"If a single enzyme is responsible for this chemical process, its reproduction on a large scale using biotechnological methods should be achievable," said Cambridge's Paolo Bombelli, first author of the study published today in the journal Current Biology.

"This discovery could be an important tool for helping to get rid of the polyethylene plastic waste accumulated in landfill sites and oceans."

Polyethylene is largely used in packaging, and accounts for 40% of total demand for plastic products across Europe – where up to 38% of plastic is discarded in landfills. People around the world use around a trillion plastic bags every single year.

Generally speaking, plastic is highly resistant to breaking down, and even when it does the smaller pieces choke up ecosystems without degrading. ̽��ֱ��environmental toll is a heavy one.

Yet nature may provide an answer. ̽��ֱ��beeswax on which wax worms grow is composed of a highly diverse mixture of lipid compounds: building block molecules of living cells, including fats, oils and some hormones.

̽��ֱ��researchers say it is likely that digesting beeswax and polyethylene involves breaking similar types of chemical bonds, although they add that the molecular detail of wax biodegradation requires further investigation.

“Wax is a polymer, a sort of ‘natural plastic,’ and has a chemical structure not dissimilar to polyethylene,” said CSIC’s Bertocchini, the study’s lead author.

̽��ֱ��researchers conducted spectroscopic analysis to show the chemical bonds in the plastic were breaking. ̽��ֱ��analysis showed the worms transformed the polyethylene into ethylene glycol, representing un-bonded ‘monomer’ molecules.

To confirm it wasn’t just the chewing mechanism of the caterpillars degrading the plastic, the team mashed up some of the worms and smeared them on polyethylene bags, with similar results.

“ ̽��ֱ��caterpillars are not just eating the plastic without modifying its chemical make-up. We showed that the polymer chains in polyethylene plastic are actually broken by the wax worms,” said Bombelli.

“ ̽��ֱ��caterpillar produces something that breaks the chemical bond, perhaps in its salivary glands or a symbiotic bacteria in its gut. ̽��ֱ��next steps for us will be to try and identify the molecular processes in this reaction and see if we can isolate the enzyme responsible.”

As the molecular details of the process become known, the researchers say it could be used to devise a biotechnological solution on an industrial scale for managing polyethylene waste.

Added Bertocchini: “We are planning to implement this finding into a viable way to get rid of plastic waste, working towards a solution to save our oceans, rivers, and all the environment from the unavoidable consequences of plastic accumulation.”

A common insect larva that eats beeswax has been found to break down chemical bonds in the plastic used for packaging and shopping bags at uniquely high speeds. Scientists say the discovery could lead to a biotechnological approach to the polyethylene waste that chokes ocean ecosystems and landfill sites.

̽��ֱ��caterpillar produces something that breaks the chemical bond, perhaps in its salivary glands or a symbiotic bacteria in its gut

Paolo Bombelli

̽��ֱ��research team.

Close-up of wax worm next to biodegraded holes in a polyethylene plastic shopping bag from a UK supermarket as used in the experiment.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Cellulose: new understanding could lead to tailored biofuels

fpjl2 — Thu, 09 Jun 2016 09:38:08 +0000

Scientists have identified new steps in the way plants produce cellulose, the component of plant cell walls that provides strength, and forms insoluble fibre in the human diet.

̽��ֱ��findings could lead to improved production of cellulose and guide plant breeding for specific uses such as wood products and ethanol fuel, which are sustainable alternatives to fossil fuel-based products.

Published in the journal Nature Communications today, the work was conducted by an international team of scientists, led by the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Melbourne.

"Our research identified several proteins that are essential in the assembly of the protein machinery that makes cellulose," said Melbourne's Prof Staffan Persson.

“We found that these assembly factors control how much cellulose is made, and so plants without them can not produce cellulose very well and the defect substantially impairs plant biomass production. ̽��ֱ��ultimate aim of this research would be breed plants that have altered activity of these proteins so that cellulose production can be improved for the range of applications that use cellulose including paper, timber and ethanol fuels."

̽��ֱ��newly discovered proteins are located in an intracellular compartment called the Golgi where proteins are sorted and modified.

“If the function of this protein family is abolished the cellulose synthesizing complexes become stuck in the Golgi and have problems reaching the cell surface where they normally are active” said the lead authors of the study, Drs. Yi Zhang (Max-Planck Institute for Molecular Plant Physiology) and Nino Nikolovski ( ̽��ֱ�� of Cambridge).

“We therefore named the new proteins STELLO, which is Greek for to set in place, and deliver.”

“ ̽��ֱ��findings are important to understand how plants produce their biomass,” said Professor Paul Dupree from the ̽��ֱ�� of Cambridge's Department of Biochemistry.

“Greenhouse-gas emissions from cellulosic ethanol, which is derived from the biomass of plants, are estimated to be roughly 85 percent less than from fossil fuel sources. Research to understand cellulose production in plants is therefore an important part of climate change mitigation.”

“In addition, by using cellulosic plant materials we get around the problem of food-versus-fuel scenario that is problematic when using corn as a basis for bioethanol.”

“It is therefore of great importance to find genes and mechanisms that can improve cellulose production in plants so that we can tailor cellulose production for various needs.”

Previous studies by Profs. Persson’s and Dupree’s research groups have, together with other scientists, identified many proteins that are important for cellulose synthesis and for other cell wall polymers.

With the newly presented research they substantially increase our understanding for how the bulk of a plant’s biomass is produced and is therefore of vast importance to industrial applications.

̽��ֱ��work was funded, in part, by the BBSRC and was conducted with the BBSRC Sustainable Bioenergy Centre Cell Wall Sugars Programme.

Adapted from a ̽��ֱ�� of Melbourne press release.

In the search for low emission plant-based fuels, new research may help avoid having to choose between growing crops for food or fuel.

By using cellulosic plant materials we get around the problem of food-versus-fuel scenario that is problematic when using corn as a basis for bioethanol

Paul Dupree

Nino Nikolovski and Paul Dupree

Arabidopsis seeds exude slime that is attached to the seed by cellulose. On the left is a seed with normal slime stained pink, but on the right, in the stello mutant, the slime is lost because the cellulose is missing.

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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World’s first artificial enzymes created using synthetic biology

tdk25 — Mon, 01 Dec 2014 16:00:00 +0000

A team of researchers have created the world’s first enzymes made from artificial genetic material.

̽��ֱ��synthetic enzymes, which are made from molecules that do not occur anywhere in nature, are capable of triggering chemical reactions in the lab.

̽��ֱ��research is published in the journal Nature and promises to offer new insights into the origins of life, as well as providing a potential starting point for an entirely new generation of drugs and diagnostics. In addition, the authors speculate that the study increases the range of planets that could potentially host life.

All life on Earth depends on the chemical transformations that enable cellular function and the performance of basic tasks, from digesting food to making DNA. These are powered by naturally-occurring enzymes which operate as catalysts, kick-starting the process and enabling such reactions to happen at the necessary rate.

For the first time, however, the research shows that these natural biomolecules may not be the only option, and that artificial enzymes could also be used to power the reactions that enable life to occur.

̽��ֱ��findings build on previous work in which the scientists, from the MRC Laboratory of Molecular Biology in Cambridge and the ̽��ֱ�� of Cambridge, created synthetic molecules called “XNAs”. These are entirely artificial genetic systems that can store and pass on genetic information in a manner similar to DNA.

Using these XNAs as building blocks, the new research involved the creation of so-called “XNAzymes”. Like naturally occurring enzymes, these are capable of powering simple biochemical reactions.

Dr Alex Taylor, a Post-doctoral Researcher at St John’s College, ̽��ֱ�� of Cambridge, who is based at the MRC Laboratory and was the study’s lead author, said: “ ̽��ֱ��chemical building blocks that we used in this study are not naturally-occurring on Earth, and must be synthesised in the lab. This research shows us that our assumptions about what is required for biological processes – the ‘secret of life’ – may need some further revision. ̽��ֱ��results imply that our chemistry, of DNA, RNA and proteins, may not be special and that there may be a vast range of alternative chemistries that could make life possible.”

Every one of our cells contains thousands of different enzymes, many of which are proteins. In addition, however, nucleic acids – DNA and its close chemical cousin, RNA – can also form enzymes. ̽��ֱ��ribosome, the molecular machine which manufactures proteins within all cells, is an RNA enzyme. Life itself is widely thought to have begun with the emergence of a self-copying RNA enzyme.

Dr Philipp Holliger, from the MRC Laboratory of Molecular Biology, said: “Until recently it was thought that DNA and RNA were the only molecules that could store genetic information and, together with proteins, the only biomolecules able to form enzymes.”

“Our work suggests that, in principle, there are a number of possible alternatives to nature’s molecules that will support the catalytic processes required for life. Life’s ‘choice’ of RNA and DNA may just be an accident of prehistoric chemistry.”

“ ̽��ֱ��creation of synthetic DNA, and now enzymes, from building blocks that don’t exist in nature also raises the possibility that if there is life on other planets it may have sprung up from an entirely different set of molecules, and widens the possible number of planets that might be able to host life.”

̽��ֱ��group’s previous study, carried out in 2012, showed that six alternative molecules, called XNAs, could store genetic information and evolve through natural selection. Expanding on that principle, the new research identified, for the first time, four different types of synthetic catalyst formed from these entirely unnatural building blocks.

These XNAzymes are capable of catalysing simple reactions, like cutting and joining strands of RNA in a test tube. One of the XNAzymes can even join strands together, which represents one of the first steps towards creating a living system.

Because their XNAzymes are much more stable than naturally occurring enzymes, the scientists believe that they could be particularly useful in developing new therapies for a range of diseases, including cancers and viral infections, which exploit the body’s natural processes.

Dr Holliger added: “Our XNAs are chemically extremely robust and, because they do not occur in nature, they are not recognised by the body’s natural degrading enzymes. This might make them an attractive candidate for long-lasting treatments that can disrupt disease-related RNAs.”

Professor Patrick Maxwell, Chair of the MRC’s Molecular and Cellular Medicine Board and Regius Professor of Physic at the ̽��ֱ�� of Cambridge, said: “Synthetic biology is delivering some truly amazing advances that promise to change the way we understand and treat disease. ̽��ֱ��UK excels in this field, and this latest advance offers the tantalising prospect of using designer biological parts as a starting point for an entirely new class of therapies and diagnostic tools that are more effective and have a longer shelf-life.”

Funders of the research included the MRC, European Science Foundation and the Biotechnology and Biological Sciences Research Council.

Enzymes made from artificial molecules which do not occur anywhere in nature have been shown to trigger chemical reactions in the lab, challenging existing views about the conditions that are needed to enable life to happen.

Our assumptions about what is required for biological processes – the ‘secret of life’ – may need some further revision

Alex Taylor

A. Taylor

̽��ֱ��study built on previous work which created synthetic molecules known as “XNA”, then used these as the basis of creating so-called “XNAzymes”.

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Metabolism may have started in our early oceans before the origin of life

cjb250 — Fri, 25 Apr 2014 15:12:59 +0000

In a study funded by the Wellcome Trust and the European Research Council researchers at the ̽��ֱ�� of Cambridge reconstructed the chemical make-up of the Earth’s earliest ocean in the laboratory. ̽��ֱ��team found the spontaneous occurrence of reaction sequences which in modern organisms enable the formation of molecules essential for the synthesis of metabolites. These organic molecules, such as amino acids, nucleic acids and lipids, are critical for the cellular metabolism seen in all living organisms

̽��ֱ��detection of one of the metabolites, ribose 5-phosphate, in the reaction mixtures is particularly noteworthy, as RNA precursors like this could in theory give rise to RNA molecules that encode information, catalyze chemical reactions and replicate.

It was previously assumed that the complex metabolic reaction sequences, known as metabolic pathways, which occur in modern cells, were only possible due to the presence of enzymes. Enzymes are highly complex molecular machines that are thought to have come into existence during the evolution of modern organisms. However, the team’s reconstruction reveals that metabolism-like reactions could have occurred naturally in our early oceans, before the first organisms evolved.

Life on Earth began during the Archean geological eon almost 4 billion years ago in iron-rich oceans that dominated the surface of the planet. This was an oxygen-free world, pre-dating photosynthesis, when the redox state of iron was different and much more soluble to act as potential catalysts. In these oceans, iron, other metals and phosphate facilitated a series of reactions which resemble the core of cellular metabolism occurring in the absence of enzymes.

̽��ֱ��findings suggest that metabolism predates the origin of life and evolved through the chemical conditions that prevailed in the worlds earliest oceans.

“Our results show that reaction sequences that resemble two essential reaction cascades of metabolism, glycolysis and the pentose-phosphate pathways, could have occurred spontaneously in the earth’s ancient oceans,” says Dr Markus Ralser from the Department of Biochemistry at the ̽��ֱ�� of Cambridge and the National Institute for Medical Research, who led the study.

“In our reconstructed version of the ancient Archean ocean, these metabolic reactions were particularly sensitive to the presence of ferrous iron which was abundant in the early oceans, and accelerated many of the chemical reactions that we observe. We were surprised by how specific these reactions were,” he added.

̽��ֱ��conditions of the Archean ocean were reconstructed based on the composition of various early sediments described in the scientific literature which identify soluble forms of iron as one of the most frequent molecules present in these oceans.

Alexandra Turchyn from the Department of Earth Sciences at the ̽��ֱ�� of Cambridge, one of the co-authors of the study said: “We are quite certain that the earliest oceans contained no oxygen, and so any iron present would have been soluble in these oxygen-devoid oceans. It’s therefore possible that concentrations of iron could have been quite high”.

̽��ֱ��different metabolites were incubated at temperatures of 50-90˚C, similar to what might be expected close to the hydrothermal vents of an oceanic volcano. These temperatures would not support the activity of conventional protein enzymes. ̽��ֱ��chemical products were separated and analyzed by liquid chromatography tandem mass spectrometry.

Some of the observed reactions could also take place in water but were accelerated by the presence of metals that served as catalysts. “In the presence of iron and other compounds found in the oceanic sediments, we observed 29 metabolism-like chemical reactions, including those that produce some of the essential chemicals of metabolism, for example precursors to the building blocks of proteins or RNA,” says Dr Ralser.

“These results indicate that the basic architecture of the modern metabolic network could have originated from the chemical and physical constraints that existed on Earth billions of years ago.”

Copy adapted from an original press release from the Wellcome Trust.

Reference
Keller et al. (2014) Mol Syst Biol 10:725. Non-enzymatic glycolysis and pentose phosphate pathway-like reactions in a plausible Archean ocean

̽��ֱ��chemical reactions behind metabolism – the processes that occur within all living organisms in order to sustain life – may have formed spontaneously in the Earth’s early oceans, according to research published today.

̽��ֱ��basic architecture of the modern metabolic network could have originated from the chemical and physical constraints that existed on Earth billions of years ago

Markus Ralser

Dhilung Kirat

After storm

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Everything we think we know – and know we don’t know – about cancer

amb206 — Wed, 06 Jun 2012 08:08:42 +0000

For 20 years or so Dr Robin Hesketh, Senior Lecturer in the Department of Biochemistry at Cambridge ̽��ֱ��, thought about writing a book. What he had in mind was one “that explained in the most simple way everything we think we know about cancer”. But he put it off, concentrating instead on experiments aimed at finding ways of stopping tumours growing and teaching Cambridge students about cells and how they signal to themselves and to each other. Then, one wet Sunday in 2008, he sat down at home and wrote the first words of Betrayed by Nature: ̽��ֱ��War on Cancer (Palgrave Macmillan, 2012).

Everything we think we know about cancer turns out to be quite a lot. We know that one in every three or four of us will get cancer during our lifetime – but that some of types can now be treated with very high success rates. We know that cancers are abnormal growths of cells – neoplasms – and that we’ve all got them in some form. Moles are unusual clumps of cells but are – almost always – unthreatening. We know that cancers can subvert our immune system, not only leaving us vulnerable to infection, but turning it from protector to traitor, giving succour to the neoplasm that can kill us. And we know that the lethality of these growths comes mainly from their acquiring the means to move home and, in wandering around the body, find a new locale in which to settle (a process known as metastasis).

Betrayed by Nature starts with a stroll through the history of cancer. As early as 1,600 BC the Egyptians were aware of conditions for which there was no treatment. Around 400 BC Hippocrates came up with the word carcinoma to describe tumours with a high density of blood vessels. Some 600 years later Galen, another Greek, is credited as the first person to use the word cancer (Latin for crab).

It wasn’t until the 18^th century that physicians began to link cancers to occupation and lifestyle. In 1713 Bernardino Ramazzini noted that cervical cancer was rare in nuns yet they were prone to breast cancer. A few years later Percival Pott concluded that sweeps (many were boys who were sent up chimneys naked) developed cancer of the scrotum as a result of soot lodging in the folds of skin. And then in 1866 Paul Broca, having studied his wife’s family tree, became the first to suggest it might be possible to inherit breast cancer. Even before those observations, the 17^th century pioneer Robert Hooke - a polymath whose inventive mind embraced physics, astronomy and the first blood transfusions - had identified the cell as the basic unit of life, laying the foundations for the field of cell biology.

Hesketh’s historical saunter leads us to the modern era of molecular biology. Launched by the revelation of the double helical structure of DNA in 1953, this field has seen an explosion of knowledge as the basic machinery of life has been unveiled. At its heart is the instruction code enshrined in DNA, in humans a sequence of three thousand million bases, and ‘DNA makes RNA makes protein’ has become ‘the central dogma’. With this has come the demonstration that thousands of diseases arise from corruptions in the code that are manifested in abnormal proteins. A well-known example is cystic fibrosis, an ultimately fatal condition caused by a mutant form of just one protein made in the lung.

Cancers too are mutation-driven diseases but with two crucial differences. ̽��ֱ��first is that cancers are driven by not one but several mutations acting in concert. As tumours develop they accumulate thousands of random mutations from which groups of perhaps half a dozen provide the driving force. ̽��ֱ��second is that the effect of ‘driver’ mutations is to cause cells to reproduce themselves abnormally. Many cells in the body replicate rapidly while some scarcely replicate at all after initial development is complete, and others can be ‘turned on’ when required, for example to repair injured tissue. ̽��ֱ��problem caused by cancer mutations is that they make cells multiply (in cell biology, multiplication is division) either too rapidly or at a time when, or in a place where, they shouldn’t.

Hesketh paints a picture of the infinity of flexible shapes that proteins can form and then illustrates the four major types of mutation that can act as cancer drivers. From this, the story moves to the effect of such mutants on the way cells behave – how normal cells are seduced into ignoring signals they should respond to, how cancer cells avoid suicide signals so that they survive with their mutant accelerators and defective brakes, adjusting their metabolism and co-opting nearby normal cells to promote their extravagant lifestyle, ensuring that survival and expansion of the tumour dominates. And then finally and fatally, we discover what happens when cancer cells spread in the usually fatal diaspora.

Betrayed by Nature addresses the unspoken question ‘if cancer is essentially so simple, how come it’s killing seven million people a year and the 12 million new cases in 2008 is set to become 15 million by 2020, when 30 million people on the planet will have cancer of some sort?’. Part of the answer is that we persist in doing things we know will get tumours going: sunbathing without protection (especially fair-skinned people), smoking (despite trends in some countries, the figure of over five million a year that tobacco use kills now, that’s one every six seconds, will rise to over eight million a year by 2030), eating poor diets and getting fat. On top of this, there’s the fact that we’re all living longer – and the longer we stick around, the more likely we are to develop cancer. In the Bronze Age the average lifespan was 18 years. Now world-wide it’s 66 and in the UK over 80 – facts that have the curious effect of making the cancer mortality rate in India (average life expectancy 64) half that of the UK.

̽��ֱ��other – and more complicated – part of the answer lies in DNA and its extraordinary flexibility. ̽��ֱ��random game of chance is that life means that the odds are heavily against a fertilized egg making it into a human being. When it does so it will have encoded in its DNA millions of variants, not only making each of us different to one another (the basis of DNA ‘fingerprinting’) but also giving us an individual molecular canvas upon which the layering of subsequently acquired mutations will inevitably lead to cancer – if we live to be 140. ̽��ֱ��cancers that emerge are so highly individual that each is unique. Each tumour has a different genetic make-up, even though historically pathologists have classified them into distinct categories.

̽��ֱ��astonishing individuality and complexity of each tumour is being revealed in molecular detail by current DNA sequencing methods and the final instalment of this saga is all about what Hesketh now regrets describing as “the greatest revolution in the history of medicine” in the book. He comments: “I should have substituted ‘science’ for ‘medicine’ because the technical advances that have occurred since the human genome was first sequenced in 2003 have already changed how we think about cancer and how we treat it and in the end they will affect everyone on earth.” ̽��ֱ��chapter ‘Let’s Sequence Your DNA’ notes that when the project to sequence the human genome was launched at the end of the 1980s the cost estimate was $1 per base: the current figure is one millionth of that—10,000 bases for one cent. ̽��ֱ��first sequencing machines in the early 1980s managed 10 kilo bases (10,000 bases) a day; the present rate is heading towards 100 million kb per day. So the cost has gone down by a factor of one million and the speed has gone up by 10 million.

All of this means that individual tumours can now be sequenced before treatment strategies are drawn up. For a number of the major cancers, sequencing has shown that tens of thousands of mutations accumulate as the tumours evolve in a process that Hesketh likens to ‘dynamic Darwinism’ as changes in DNA that confer a growth advantage permit clones to expand and dominate. ̽��ֱ��complexity of these mutational patterns is bewildering and it is almost beyond belief that a cell can survive such ferocious assaults on its genetic integrity, yet alone that a clone may emerge with the power ultimately to overwhelm its host.

A new vista in medicine is opening up, one that for cancer has already identified the major driving mutations and thus provided focal points for the development of new drugs. In parallel with the sequencing revolution, major strides are being made in ways of visualising tumours so that they can be detected with greater sensitivity and also that the effects of drug therapy may be followed. In addition, the progressive identification of molecular ‘biomarkers’ present in circulating blood will permit tumour detection at much earlier stages than is currently possible. These efforts are driven by the fact that surgery remains the first line of defence. More than 90% of cancer deaths come from metastasis. If they can be treated before they spread, by surgery and radiotherapy, the success rates are very high.

Amazing though the developments of the last ten years are, as is always the case in science, they build on what has gone before and Betrayed by Nature highlights the tremendous strides made in the second half of the 20^th century. ̽��ֱ��pioneering work of Sidney Farber at Harvard in the 1940s produced remission of childhood leukemia. Since then other very effective treatments have evolved, as illustrated by the progressive rise in five year survival rates for breast cancer and prostate cancer to over 85% and almost 100%, respectively. One of the greatest triumphs has been the development of vaccines that are essentially 100% effective in preventing cervical carcinoma by blocking viral infection that is the cause of almost all these cancers.

̽��ֱ��optimism in Betrayed by Nature derives from the evidence that the era we are entering offers not only the possibility of making an impact on cancers that have remained intractable but that, as detection is refined and the stock of specific drugs expands, we may even contemplate the replacement of surgery by highly effective chemotherapy. But Hesketh also has some simple messages that speak directly to today’s readers. “You can avoid a lot of things in life if you really want to: football, hamburgers, sex … but you can’t avoid cancer at least coming very close to you.” As for what we can do to maximise our chances of staying well, he says: “Don’t smoke – but if you do, give up – it’s not too late!” “Eat sensibly and do a bit of exercise” And he adds: “Men especially, if you think something’s wrong, follow JBS Haldane’s advice: don’t be macho – go and see your doctor.”

Betrayed by Nature: ̽��ֱ��War on Cancer by Robin Hesketh is published by Palgrave Macmillan, 2012.

A book written for the general reader, Betrayed by Nature: ̽��ֱ��War on Cancer by Dr Robin Hesketh, sets out in plain English what goes wrong in our bodies when cells begin to replicate in an abnormal manner, and what science is doing to address the disease that kills seven million people every year.

A new vista in medicine is opening up, one that for cancer has already identified the major driving mutations and thus provided focal points for the development of new drugs.

Robin Hesketh

Dr Robin Hesketh with flourescent images of (normal) human cell lines grown in culture

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